Abstract: The objective of this MPI R21 is to support an important discovery found by this basic T cell immunologist and immune-therapist (Dr. Chrystal Paulos) and surgeon and scientist (Dr. David Neskey) research team in a Phase II clinical trial (NCT03021993) in patients with oral cavity squamous cell carcinoma (OCC). These patients were treated with Nivolumab as a novel neoadjuvant pre-surgical therapy at our institution (Hollings Cancer Center). Our unpublished work reveals that a remarkable 44% of patients responded to this therapy via pathological score. While promising, 56% of the patients remain unresponsive to this treatment. Our new data reveals that responders express higher CD26 (co-stimulatory molecule with enzyme activity) on tumor- infiltrating lymphocytes (TILs), while CD26 was far lower on TILs from non-responders. These data suggest that CD26 plays a critical role in the function and migration of antitumor T cells to the oppressive tumor microenvironment in patients responsive to PD-1 therapy. We propose to gain insight into CD26-expressing T cells in the tumor, positing that the enzymatic CD26 activity augments the function, migration and antitumor activity of human TILs (Aim 1) and that targeting this pathway can improve cancer immunotherapy in non- responders: an idea we will explore in Aim 2, using our highly clinically relevant OCC tumor models. Overall, the proposed research is expected to demonstrate that manipulation of the CD26 pathway may sufficiently induce durable immunity against advanced OCC tumors and rescue patients non-responsive to PD-1 therapy.